title: Induced differentiation of acute myeloid leukemia cells by activation of retinoid X and liver X receptors.
abstract: Use of all-trans retinoic acid (ATRA) as a differentiation agent has been limited to acute promyelocytic leukemia (APL) as non-APL leukemias are insensitive to ATRA. We recently demonstrated that the rexinoid, bexarotene, induces differentiation and therapeutic responses in patients with refractory AML. Rexinoids bind and activate retinoid X receptors (RXRs); however, rexinoids alone are incapable of activating retinoic acid receptor (RAR)/RXR complexes, suggesting that myeloid differentiation can occur independent of RAR. In this study, we demonstrate that rexinoid differentiation of AML cells is RAR independent and requires the expression of PU.1. Because of the promiscuousness of RXR with other nuclear receptors, myeloid differentiation by bexarotene with other nuclear receptor ligands was explored. Bexarotene cooperated with ATRA to enhance differentiation in some AML cell lines; however, the combination of bexarotene with the PPARγ agonist rosiglitazone did not. In contrast, bexarotene combined with liver X receptor (LXR) agonists, T0901317 or GW3965, induced potent differentiation and cytotoxicity in AML cell lines and primary human AML cells, but not in normal progenitor cells. These results suggest that RXR/LXR-regulated gene expression in normal cells is deregulated in AML cells and identifies a potential role for these agonists in differentiation therapy of non-APLs.
authors.affiliation: Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA.
authors.forename: P V
authors.initials: PV
authors.lastname: Sanchez
authors.affiliation: Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Glantz
authors.affiliation: Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Scotland
authors.affiliation: Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: M T
authors.initials: MT
authors.lastname: Kasner
authors.affiliation: Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Carroll
mesh_terms: D000077610:Bexarotene; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D000071518:Liver X Receptors; D009539:Nicotinic Acids / Q000494:pharmacology; D057093:Orphan Nuclear Receptors / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology; D047488:Retinoid X Receptors / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D015534:Trans-Activators / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology; D000099232:Proto-Oncogene Protein Spi-1; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000077610:Bexarotene; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022762:CCAAT-Enhancer-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D009539:Nicotinic Acids; D057093:Orphan Nuclear Receptors; D011518:Proto-Oncogene Proteins; D047488:Retinoid X Receptors; D013449:Sulfonamides; D013764:Tetrahydronaphthalenes; D015534:Trans-Activators; D014212:Tretinoin; D000099232:Proto-Oncogene Protein Spi-1; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C070790:CEBPE protein, human; C095104:LG 100268